Particulate medicament in an aerosol formulation with a propellant and co-propellant

ABSTRACT

This invention relates to aerosol formulations of use in the administration of medicaments by inhalation. In particular, the formulations comprise (a) 1,1,1,2-tetrafluoro-ethane or 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof as propellant, (b) 1,1,2,2,3-pentafluoropropane as co-propellant, and (c) particulate medicament. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of the pharmaceutical aerosol formulation is also described, as well as is a canister which is suitable for delivering the pharmaceutical aerosol formulation.

This application is a continuation of co-pending application Ser. No.08/849,217, filed Jul. 21, 1997 (of which the entire disclosure of thepending, prior application is hereby incorporated by reference), nowU.S. Pat. No. 6,153,173, granted Nov. 28, 2000, which itself is a 371 ofinternational application number PCT/EP95/04824, filed Dec. 8, 1995.

This invention relates to aerosol formulations of use in theadministration of medicaments by inhalation.

The use of aerosols to administer medicaments has been known for severaldecades. Such aerosols generally comprise the medicament, one or morechlorofluorocarbon propellants and either a surfactant or a solvent,such as ethanol.

The most commonly used aerosol propellants for medicaments have beenCCl₃F (propellant 11) in admixture with CCl₂F₂ (propellant 12) andCF₂Cl.CF₂Cl (propellant 114). However these propellants are now believedto provoke the degradation of stratospheric azone and there is thus aneed to provide aerosol formulations for medicaments which employ socalled “ozone-friendly” propellants.

A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventionalchlorofluorocarbons comprise hydrogen-containing chlorofluorocarbons andfluorocarbons and a number of medicinal aerosol formulations using suchpropellant systems have been disclosed in, for example, EP 0372777,WO91/04011, WO91/11173, WO91/11495, WO91/14422, WO92/00061, WO92/00062and WO92/00107.

These applications are all concerned with the preparation of pressurisedaerosols for the administration of medicaments and seek to overcome theproblems associated with the use of the new class of propellants, inparticular the problems of stability associated with the pharmaceuticalformulations prepared. These applications all propose the addition of awide range of adjuvants such as alcohols, alkanes, dimethyl ether,surfactants (including fluorinated and nonfluorinated surfactants,carboxylic acids, polyethoxylates etc) and even conventionalchlorofluorocarbon propellants in small amounts to minimise potentialozone damage.

Surprisingly, we have now found that mixtures of a non ozone-depletingpropellant and a specific fluorinated hydrocarbon may be employed aspropellant systems suitable for use in pharmaceutical aerosolcompositions.

There is thus provided in one aspect of the invention an aerosolformulation comprising:

(a) 1,1,1,2-tetrafluoroethane (CF₃CH₂F),1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃) or mixtures thereof aspropellant;

(b) 1,1,2,2,3-pentafluoropropane as co-propellant; and

(c) particulate medicament

Generally, the ratio of propellant:copropellant is in the range of about30:70 to about 95:5, preferably 50:50 to 90:10 by weight, especially50:50 to 80:20, for example 75:25 (w/w).

Medicaments which may be administered in aerosol formulations accordingto the invention include any drugs useful in inhalation therapy whichmay be presented in a form which is substantially completely insolublein the selected propellant system. Appropriate medicaments may thus beselected from, for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. dilitiazem;antiallergics, e.g. cromolyn, cromogylcate or nedocromil; antibiotics,e.g. cephalosporins, penicillins, streptomycin, sulphonamides ortetacyclines; antihistamines, e.g. methapyrilene; anti-inflammatories,e.g. beclomethasone, flunisolide, fluticasone, tipredane, budesonide,triamcinolone acetonide; antitussives, e.g. noscapine; bronchodilators,e.g. ephedrine, epinephrine, fenoterol, formoterol, isoprenaline,isoproterenol, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, repoterol, rimiterol, salbutamol, salmeterol, terbutaline or(−)-4-amino-3,5-dichloro-α[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium bromide;hormones, e.g. cortisone, hydrocortisone or prednisolone; andtherapeutic proteins and peptides, e.g. glucagon or insulin. It will beclear to a person skilled in the art that, where appropriate, themedicaments will be used in the form of salts (e.g. as alkali metal oramine salts or as acid addition salts) or as esters (e.g. lower alkylesters) or as solvates (eg hydrates) to optimise the activity and/orstability of the medicament and/or to minimise the solubility of themedicament in the propellant.

Particularly preferred medicaments for administration using aerosolformulations in accordance with the invention include bronchodilatorsand anti-inflammatory steroids of use in the treatment of asthma byinhalation to, for example salbutamol (e.g. as the sulphate), salmeterol(e.g. as the hydroxynaphthoate known as salmeterol xinafoate),beclomethasone dipropionate or a solvate thereof, fluticasone propionateor(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol.

The particle size of the particulate medicament should be such as topermit inhalation of substantially all of the medicament into the lungsupon administration of the aerosol formulation and will thus desirablybe less than 20 microns, preferably in the range 1 to 10 microns, e.g. 1to 5 microns. The particle size of the medicament may be reduced byconventional means, for example by milling or micronisation.

The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

It is desirable that the formulations of the invention contain nocomponents which may provoke the degradation of stratospheric ozone. Inparticular it is desirable that the formulations are substantially freeof chlorofluorocarbons such as CCl₃F, CCl₂F₂ and CF₃CCl₃. As used herein“substantially free” means less than 1% w/w based upon the propellantsystem, in particular less than 0.5%, for example 0.1% or less.

The propellant may optionally contain an adjuvant having a higherpolarity and/or a higher boiling point than the propellant. Polaradjuvants which may be used include (e.g. C₂₋₆) aliphatic alcohols andpolyols such as ethanol, isopropanol and propylene glycol, preferablyethanol. In general only small quantities of polar adjuvants (e.g.0.05-3.0% w/w) may be required to improve the stability of thedispersion—the use of quantities in excess of 5% w/w may tend todissolve the medicament. Formulations in accordance with the inventionmay preferably contain less than 1% w/w, e.g. about 0.1% w/w, of polaradjuvant. However, the formulations of the invention are preferablysubstantially free of polar adjuvants, especially ethanol. Suitablevolatile adjuvants include saturated hydrocarbons such as propane,n-butane, isobutane, pentane and isopentane and alkyl ethers such asdimethyl ether. In general, up to 50% w/w of the propellant may comprisea volatile adjuvant, for example 1 to 30% w/w of a volatile saturatedC₁₋₆ hydrocarbon.

Optionally, the aerosol formulations according to the invention mayfurther comprise one or more surfactants. The surfactants must bephysiologically acceptable upon administration by inhalation. Withinthis category are included surfactants such as oleic acid, sorbitantrioleate (Span ^(R)85), sorbitan mono-oleate, sorbitan monolaurate,polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitanmonooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearylpolyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, blockcopolymers of oxyethylene and oxypropylene, synthetic lecithin,diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate,isopropyl myristate, glyceryl monooleate, glyceyl monostearate, glycerylmonoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol400, cetyl pyridinium chloride, benzalkonium chloride, olive oil,glyceryl monolaurate, corn oil, cotton seed oil and sunflower seed oil.Preferred surfactants are lecithin, oleic acid and sorbitan trioleate.

An alternative class of surfactants are described in EP 0478686,especially surfactants of formula (I)

wherein n is an integer of 1 to 18, especially 2 to 12; m is an integerof 0 to 17, especially 0 to 11; and R¹, R² and R³ are each independentlya hydrogen atom or a C₁₋₄alkyl group.

Particularly preferred surfactants of formula (I) are the fluorinatedphosphatidylcholines wherein R¹, R² and R³ each represent methyl, n isan integer of 4 to 8, especially 4 or 6, and m is an integer of 4 to 10,especially 4 or 6.

If desired, the surfactant may be incorporated into the aerosolformulation in the form of a surface coating on the particulatemedicament In this case, the use of substantially non-ionic surfactantswhich have reasonable solubility in substantially non-polar solvents isfrequently advantageous since it facilitates coating of the medicamentparticles using solutions of surfactants in non-polar solvents in whichthe medicament has limited or minimal solubility.

The amount of surfactant employed in coating the particulate medicamentis desirably in the range 0.1 to 10% w/w preferably 1 to 10% w/w,relative to the medicament. Where the surfactant is present as a surfacecoating, the amount may advantageously be chosen such that asubstantially monomolecular coating of sent is formed. However, it ispreferable that the formulations of the invention are substantially freeof surfactants, i.e. contain less than an effective stabilising amountof a surfactant such as less than 0.0001% by weight of medicament.

The formulations of the invention may be prepared by dispersal of themedicament in the selected propellant and/or co-propellant in anappropriate container, e.g. with the aid of sonication. Preferably theparticulate medicament is suspended in co-propellant and filled into, asuitable container. The valve of the container is then sealed into placeand the propellant introduced by pressure filling through the valve inthe conventional manner. Surprisingly, the aerosol formulationsaccording to the invention have been found to be easily redispersed bymild agitation to provide suspensions with excellent deliverycharacteristics suitable for use in pressurised inhalers, even afterprolonged storage.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The formulations according to the invention may be filled into canisterssuitable for delivering pharmaceutical aerosol formulations. Canistersgenerally comprise a container capable of withstanding the vapourpressure of the propellant used such as a plastic or plastic-coatedglass bottle or preferably a metal can, for example an aluminium canwhich may optionally be anodised, lacquer-coated and/or plastic-coated,which container is dosed with a metering valve. The metering valves aredesigned to dewier a metered amount of the formulation per actuation andincorporate a gasket to prevent leakage of propellant through the valve.The gasket may comprise any suitable elastomeric material such as forexample low density polyethylene, chlorobutyl, black and whitebutadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitablevalves are commercially available from manufacturers well known in theaerosol industry, for example, from Valois, France (e.g. DF10, DF30,DF60), Bespak plc, UK (e.g. BK300, BK356) and 3M-Neotechnic Ltd, UK(e.g. Spraymiser™).

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method the particulate medicament is first suspended inthe co-propellant. The drug suspension is then filled into the emptycanisters, valves crimped on and then propellant is pressure filled intothe canisters through the valves in conventional manner. Typically, inbatches prepared for pharmaceutical use, each filled canister ischeck-weighed, coded with a batch number and packed into a tray forstorage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs or nasal cavity of a patient. Suitablechannelling devices comprise for example a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers aredesigned to deliver a fixed unit dosage of medicament per actuation or“puff”, for example in the range of 10 to 5000 microgram medicament perpuff.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularparticulate medicament used and the frequency of administration and willultimately be at the discretion of the attendant physician. Whencombinations of medicaments are employed the dose of each component ofthe combination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample from 1 to 8 times per day, giving for example 1,2,3 or 4 puffseach time.

The following non-limitative Examples serve to illustrate the invention.

EXAMPLE 1

Micronised salmeterol xinafoate (hydroxynaphthoate, 8.7 mg) was weighedinto a clean, dry glass bottle together with1,1,2,2,3-pentafluoropropane (1.3 g, 1 ml). The bottle was sealed bycrimping a valve in place. Propellant 1,1,1,2-tetrafluoroethane (20.7 g,17 ml) was added, under pressure, through the valve. The resultantinhaler delivers 25 μg of salmeterol xinafoate (hydroxynaphthoate) peractuation (200 75 mg actuations per bottle). The ratio of propellant(CF₃CH₂F) to co-propellant (CHF₂CF₂CH₂F) was 17:1 (v/v).

EXAMPLE 2

Micronised salmeterol xinafoate (hydroxynaphthoate, 8.7mg) was weighedinto a clean, dry glass bottle together with1,1,2,2,3-pentafluoropropane (5.2 g. 4 ml). The bottle was sealed bycrimping a valve in place. Propellant 1,1,1,2-tetrafluoroethane (17.1 g,14 ml) was added, under pressure, through the valve. The resultantinhaler delivers 25 μg of salmeterol xinafoate (hydroxynaphthoate) peractuation (200 75 mg actuations per bottle). The ratio of propellant(CF₃CH₂F) to co-propellant (CHF₂CF₂CH₂F) was 14:4 (v/v).

EXAMPLE 3

Micronised salmeterol xinafoate (hydroxynaphthoate, 4 mg) was weighedinto a clean, dry aluminium aerosol canister (8 ml) together withco-propellant 1,1,2,2,3-pentafluoropropane (2 g). The canister wassealed by crimping a valve in place and propellant1,1,1,2-tetrafluoroethane (10 g) was added, under pressure, through thevalve. The resultant inhaler delivers 25 μg of salmeterolhydroxynaphthoate per actuation (120 75 mg actuations per can).

EXAMPLES 4 TO 7

Inhalers were prepared as described in Example 3 containing propellant(CF₃CH₂F) to co-propellant (CHF₂CF₂CH₂F) in the ratios of 9:3, 8:4, 7:5and 6:6 (w/w) (Examples 4, 5, 6 and 7 respectively).

EXAMPLE 8

Micronised salbutamol (base) (24 mg) is homogenised with the aid ofsonication in a solution of oleic acid (2.4 mg) in the co-propellant1,1,2,2,3-pentafluoropropane (4.7 g) and filled into a clean, dryaluminium aerosol canister. The canister is sealed by crimping a valvein place. Propellant 1,1,1,2-tetrafluoroethane (14.1 g) is added, underpressure, through the valve.

The resultant inhaler delivers 100 microgram salbutamol per 75 mgactuation. The ratio of propellant (CF₃CH₂F) to co-propellant(CHF₂CF₂CH₂F) was 75:25 (w/w).

EXAMPLES 9 TO 11

Inhalers are prepared as described in Example 8 containing propellant(CF₃CH₂F) and co-propellant (CHF₂CF₂CH₂F) in the ratios 70:30, 50:50 and95:5 (w/w) (Examples 9, 10 and 11 respectively).

EXAMPLE 12

Micronised salbutamol (base) (24 mg) is homogenised with the aid ofsonication in a solution of oleic acid (2.4 mg) in the co-propellant1,1,2,2,3-pentafluoropropane (5.3 g) and filled into a clean, dryaluminium aerosol canister. The canister is sealed by crimping a valvein place. Propellant 1,1,1,2,3,3,3-heptafluoro-n-propane (15.9 g) isadded, under pressure, through the valve. The resultant inhaler delivers100 microgram salbutamol per 75 mg actuation. The ratio of propellant(CF₃CHFCF₃) to co-propellant (CHF₂CF₂CH₂F) was 75:25 (w/w).

EXAMPLES 13 TO 15

Inhalers are prepared as described in Example 12 containing propellant(CF₃CHFCF₃) to co-propellant (CHF₂CF₂CH₂F) in the ratios 70:30, 50:50and 95:5 (w/w) (Examples 13, 14 and 15 respectively).

EXAMPLE 16

Micronised fluticasone propionate (4 mg) is weighed into a clean, dryaluminium aerosol canister (8 ml) together with co-propellant1,1,2,2,3-pentafluoropropane (3.1 g). The canister is sealed by crimpinga valve in place. Propellant 1,1,1,2-tetrafluoroethane (9.3 g) is added,under pressure, through the valve. The resultant inhaler delivers 25 μgof fluticasone propionate per actuation (120 75 mg actuations per can).The ratio of propellant (CF₃CH₂F) to co-propellant (CHF₂CF₂CH₂F) is 9:3w/w.

EXAMPLE 17

Micronised salmeterol xinafoate (hydroxynaphthoate, 4 mg) and micronisedfluticasone propionate (8 mg) are weighed into a clean, dry aluminiumaerosol canister (8 ml) together with co-propellant1,1,2,2,3-pentafluoropropane (3.1 g). The canister is sealed by crimpinga valve in place. Propellant 1,1,1,2-tetrafluoroethane (9.3 g) is added,under pressure, through the valve. The resultant inhaler delivers 25 μgsalmeterol xinafoate (hydroxynaphthoate) and 50 μg fluticasonepropionate per actuation (120 75 mg actuations per can). The ratio ofpropellant (CF₃CH₂F) to co-propellant (CHF₂CF₂CH₂F) is 9:3 w/w.

What is claimed is:
 1. A pharmaceutical aerosol formulation comprising(a) 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane ormixtures thereof as propellant; (b) 1,1,2,2,3-pentafluoropropane asco-propellant; and (c) particulate medicament; wherein the particulatemedicament is present in an amount of 0.005-10% w/w relative to thetotal weight of formulation and wherein the particle size of theparticulate medicament is less than 20 microns.
 2. A formulationaccording to claim 1 wherein the ratio of propellant:co-propellant isabout 30:70 to about 95:5 by weight.
 3. A formulation according to claim2 wherein the ratio of propellant:co-propellant is about 50:50 to about80:20 by weight.
 4. A formulation according to claim 1 wherein thepropellant comprises 1,1,1,2-tetrafluoroethane.
 5. A formulationaccording to claim 1 wherein the propellant comprises1,1,1,2,3,3,3-heptafluoro-n-propane.
 6. A formulation according to claim1 wherein the medicament is an anti-allergic, a bronchodilator or ananti-inflammatory steroid.
 7. A formulation according to claim 1 whereinthe medicament is salmeterol xinafoate.
 8. A formulation according toclaim 1 wherein the medicament is salbutamol sulphate.
 9. A formulationaccording to claim 1 wherein the medicament is fluticasone propionate.10. A formulation according to claim 1 wherein the medicament isbeclomethansone dipropionate of a physiologically acceptable solvatethereof.
 11. A formulation according to claim 1 wherein the medicamentis formoterol, cromoglycate, terbutaline, repoterol or(−)-4amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzemethanolbudesonide, triamcinolone acetonide or a physiologically acceptable saltor solvate thereof.
 12. A formulation according to claim 1 wherein themedicament is present in an amount of 0.01 to 1% w/w relative to thetotal weight of the formulation.
 13. A formulation according to claim 1which contains two or more particulate medicaments.
 14. A formulationaccording to claim 13 which contains salbutamol or salmeterol or aphysiologically acceptable salt thereof in combination with ananti-inflammatory steroid or an anti-allergic.
 15. A formulationaccording to claim 14 which contains salmeterol or salbutamol or aphysiologically acceptable salt thereof in combination with fluticasonepropionate or beclomethasone dipropionate or a physiologicallyacceptable solvate thereof.
 16. A formulation according to claim 1comprising an adjuvant having one or both of the properties of higherpolarity and higher boiling point relative to that of the propellant.17. A formulation according to claim 16 wherein the adjuvant having ahigher polarity than the propellant is present in an amount of 0.05 to5% w/w based upon the propellant and co-propellant.
 18. A formulationaccording to claim 1 comprising a surfactant.
 19. A canister suitablefor delivering a pharmaceutical aerosol formulation which comprises acontainer capable of withstanding the vapour pressure of the propellantused which container is closed with a metering valve and contains apharmaceutical aerosol formulation which comprises (a)1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane ormixture thereof as propellant, (b) 1,1,2,2,3-pentafluoropropane asco-propellant, and (c) a particulate medicament; wherein the particulatemedicament is present in an amount of 0.005-10% w/w relative to thetotal weight of formulation and wherein the particle size of theparticulate medicament is less than 20 microns.
 20. A canister accordingto claim 19 wherein the container is a metal can.
 21. A canisteraccording to claim 20 wherein the container is an aluminium can.
 22. Acanister according to claim 20 wherein the container is plastics-coated.23. A metered dose inhaler which comprises a canister according to claim19 fitted into a suitable channelling device.
 24. A method of treatingrespiratory disorders which comprises administration by inhalation of aneffective amount of a pharmaceutical aerosol formulation according toclaim 1.